Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors

  • ACS Med Chem Lett. 2016 Jun 25;7(8):802-6. doi: 10.1021/acsmedchemlett.6b00208.
Zongxing Qiu  1 ,  Bernd Kuhn  2 ,  Johannes Aebi  2 ,  Xianfeng Lin  1 ,  Haiyuan Ding  1 ,  Zheng Zhou  1 ,  Zhiheng Xu  1 ,  Danqing Xu  1 ,  Li Han  1 ,  Cheng Liu  1 ,  Hongxia Qiu  1 ,  Yuxia Zhang  1 ,  Wolfgang Haap  2 ,  Claus Riemer  2 ,  Martin Stahl  2 ,  Ning Qin  1 ,  Hong C Shen  1 ,  Guozhi Tang  1
Affiliations
  • 1. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Shanghai , 720 Cailun Road, Shanghai 201203, China.
  • 2. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
PMID: 27563406 DOI: 10.1021/acsmedchemlett.6b00208
Abstract

ATG4B or autophagin-1 is a cysteine protease that cleaves ATG8 family proteins. ATG4B plays essential roles in the autophagosome formation and the Autophagy pathway. Herein we disclose the design and structural modifications of a series of fluoromethylketone (FMK)-based peptidomimetics as highly potent ATG4B inhibitors. Their structure-activity relationship (SAR) and protease selectivity are also discussed.

Keywords
ATG4B; autophagy; covalent inhibitor; fluoromethylketone; peptidomimetics.
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